How to Terrify the Fearless

A rare genetic condition that leaves people unable to feel fear provides clues about which regions in the brain regulate the emotion — and which may not.

Until recently, SM, a 44 year-old mother of three, was completely fearless. She has casually picked up large snakes that terrified her children, and tried to touch tarantulas despite being warned about their painful bites. When a mugger put a knife to her throat, she reacted with such eerie coolness that the man simply let her go.

SM has Urbach-Wiethe disease, a genetic disorder that only affects a few hundred people worldwide. It progressively destroys the amygdala, the almond-shaped part of the brain that researchers believe is the anatomical seat of fear. While SM did feel some fear during her childhood before the disease progressed, after age 10, she apparently could not be frightened.

While participating in a study about the role of the amygdala in fear, however, SM felt panic and terror for the first time since youth. She was gasping for breath, trembling and calling out in fright. And her experience — along with those of two other patients with the same disease — has shown for the first time that the amygdala may not be so essential to triggering the emotion. The results of the study, which was led by John Wemmie of the University of Iowa and published in Nature Neuroscience, may offer insight into the way we react to different kinds of fear, and reveal what drives panic disorder.

SM had participated in a previous study, involving potentially terrifying experiences with snakes, spiders, an amusement park haunted house and horror films. None of them frightened her, and she enjoyed the films. But in the new research, scientists may have finally found her fear trigger. SM, along with the two other patients with the same disease, inhaled carbon dioxide, the gas that we normally exhale which each breath. At the concentration used in the study, the gas produces “air hunger,” or the sense of having an oxygen deficit, making people gasp for breath. Not surprisingly, this feeling of suffocation is terrifying. Carbon dioxide has long been known to induce panic attacks and some researchers have theorized that one cause of panic attacks is basically the brain sending an alarm about impending suffocation. It did for all three of the Urbach-Wiethe patients.

“To the best of our knowledge, this was the first time patient SM experienced fear in any setting, laboratory or otherwise [since childhood],” the authors write. The study found that all three of the patients experienced panic attacks when inhaling the gas, some feeling so anxious that they ripped the masks from their faces. In contrast, of 12 normal controls included in the study, only three panicked, suggesting that the Urbach-Wiethe patients were more susceptible to this sort of fear.

[She] started to frantically wave her hand near the mask about 8 seconds after inhalation, and then screamed for help. “It felt like my throat was closing up … I couldn’t breathe,” she told the researchers in an interview afterwards. When asked how it had made her feel, she replied: “Panic, mostly, because I didn’t know what the hell was going on.” She described the feeling as the worst one she’d ever had, and expressed surprise at her reaction, because she couldn’t remember having reacted in that way ever before.

But why was SM able to feel fear of suffocation in this experiment, while not being panicked by a mugger? And without a properly functioning amygdala, what parts of the brain drove this reaction?

The authors note that all of the other fear-inducing experiences that they tried generally involved external threats, with menaces like snakes or scary strangers that have to be sensed by organs like the eyes and the ears and indicate possible dangers. In contrast, carbon dioxide is detected as a sign of a threat coming from within the body— a lack of oxygen. Systems devoted to detecting internal states like lack of air may not rely on the amygdala to cause fear, utilizing other regions instead.

This difference was evident in the way the participants reacted to the second session with the carbon dioxide gas. They were exposed to the gas at least two different times — the second time, they knew viscerally how scary it could be. But while the normal participants showed increased heart rate and other signs of anxiety in anticipation of the panic they would feel when the researchers were readying the mask, the patients with damaged amygdalas either showed fewer signs of anticipatory anxiety or none at all.

That makes sense, the researchers say, if the amygdala is primarily responsible for predicting and processing potential threats from the outside world. “These results are consistent with the notion that the amygdala detects potential danger in the external environment and physiologically prepares the organism to confront the threat,” the authors write.

In fact, the researchers found that the receptors that detect internal alerts send signals to regions other than the amygdala. And the receptors that detect low oxygen themselves are located in multiple brain areas, not just in the amygdala alone, which may explain why the fear among the patients, when they felt it, was more pronounced that that felt by the normal controls.

The findings also help to explain some apparently paradoxical research about the amygdala and panic disorder. Despite work showing that the region is important in generating fear, some studies have found that people with panic disorder have smaller and less active amygdalas, instead of the larger and over-activated fear-related area that might be expected. The latest data “raises the possibility that loss of amygdala function might contribute to the development of panic disorder,” the researchers write. In other words, the amygdala may be needed to tamp down fear, not just anticipate it or trigger some types of terror.

That information could help doctors to develop better ways to handle not just panic attacks but other types of potentially debilitating fear as well, by providing new brain processes to target.